cis-5-Hydroxy-2-piperidinecarboxylic acid is a useful intermediate for pharmaceuticals. However, since this compound has 2 asymmetric carbons, 4 kinds of isomers are present, and selective synthesis of a single kind of isomer, or single kind of diastereomer, is very difficult. Thus, improvement of the purity by separation of unnecessary isomers, or purification, by chemical conversion is necessary.
For example, methods for obtaining cis-5-hydroxy-2-piperidinecarboxylic acid by introduction of a hydroxyl group to 2-piperidinecarboxylic acid by hydroxylation reaction using a microorganism or enzyme have been reported. However, it has been reported that a compound having a substituted hydroxyl group at another position, such as a 3-position-hydroxylated compound, may be produced as a by-product in addition to the compound of interest, cis-5-hydroxy-2-piperidinecarboxylic acid (Non-patent Document 1). Separation of the by-product is not described in the document. A method in which 5-hydroxy-2-piperidinecarboxylic acid is synthesized from 5-hydroxylysine by enzymatic reaction has also been reported (Patent Document 1), but the document does not describe separation of the generated cis/trans isomers. In a report describing synthesis of 5-hydroxy-2-piperidinecarboxylic acid from 5-hydroxylysine by a method similar to the method of Patent Document 1 (Patent Document 2), isomers are separated using an ion-exchange column. Since this method requires use of excessive amounts of a filler and eluent with respect to the substrate, the method is not realistic from the viewpoint of industrial production.
Thus, there is no known method by which a necessary stereoisomer can be selectively obtained with high purity from cis-5-hydroxy-2-piperidinecarboxylic acid synthesized using a microorganism or enzyme.
There are known chemical synthesis methods using, as a material, L-amino acid, in which the stereochemistry of one of the two asymmetric carbons, the 2-position carbon, can be fixed. For example, a method using L-pyroglutamic acid as a material (Patent Document 3) has been reported. This method requires use of an iridium catalyst, which is expensive, for formation of a piperidine ring, which is problematic. Methods using L-glutamic acid as a material (Non-patent Documents 2 and 3) and a method using a proline derivative as a material (Non-patent Document 4) have also been reported, but all of these methods require use of a diazo compound, which is highly risky, and also require a multistep complex process. Moreover, for separation of (2S,5S)-5-hydroxy-2-piperidinecarboxylic acid, the reaction is carried out via 5-oxo-2-piperidinecarboxylic acid to preferentially obtain the (2S,5S) compound by its reduction (Non-patent Document 4). This requires separation using a silica gel column for removal of impurities such as isomers. Because of the load of this process, this method is not industrially satisfactory.
It is also known that (2S,5S)—N-benzyloxycarbonyl-5-hydroxy-2-piperidinecarboxylic acid and its esters are lactonized to give benzyl (1S,4S)-5-aza-2-oxa-3-oxobicyclo[2.2.2]octane-5-carboxylate (Non-patent Documents 4 and 5). These documents on lactonization do not mention about impurities such as isomers, and the effects of purification by these methods have been unclear. Non-patent Document 4 describes that benzyl (1S,4S)-5-aza-2-oxa-3-oxobicyclo[2.2.2]octane-5-carboxylate was obtained as an oily substance after purification with a silica gel column. Non-patent Document 5 describes that crystallization of benzyl (1S,4S)-5-aza-2-oxa-3-oxobicyclo[2.2.2]octane-5-carboxylate occurs, but, since the lactonization is carried out using cis-5-hydroxy-2-piperidinecarboxylic acid as a material, behavior of impurities such as isomers and the effect of purification are not clear. There is a report describing separation of a cis/trans mixture of methyl N-benzyloxycarbonyl-5-hydroxy-2-piperidinecarboxylate by acid treatment (Non-patent Document 3), but, since the compound was a carboxylic acid ester, it was impossible to separate lactone obtained from the cis isomer from the ester of the trans isomer by a simple method such as solvent extraction. Moreover, Non-patent Document 3 does not describe the yield in this process. When the present inventors studied this method, the yield of the lactone was low because of occurrence of a remarkable side reaction between lactone obtained from the cis isomer (benzyl (1S,4S)-5-aza-2-oxa-3-oxobicyclo[2.2.2]octane-5-carboxylate)) and the residual trans isomer ((2S,5R)—N-benzyloxycarbonyl-5-hydroxy-2-piperidinecarboxylic acid ester).
As described above, there are problems to be solved for industrial production of highly pure cis-5-hydroxy-2-piperidinecarboxylic acid by an inexpensive method.